Abstract Coronary artery disease is the leading cause of death and morbidity world-wide. Metabolic shifts and oxidative stress that occur in the myocardium during the phases of ischemia and reperfusion cause myocardial injury, and play a pivotal role in the development and progression of myocardial damage and heart failure (HF). Humanin (HN), a novel small peptide generated by mitochondria, has been shown to exhibit strong cytoprotection in many diseases with increased oxidative stress including Alzheimer?s disease, atherosclerosis, myocardial and cerebral ischemia, and type 2 diabetes. Our group has demonstrated that administration of HN results in a decrease in infarct size and preservation of cardiac function in a mouse model of myocardial ischemia-reperfusion (MI-R) injury. Additionally, our preliminary data presented in this grant submission shows that HN administration results in: 1) infarct size reduction following MI-R injury in clinically relevant swine model; 2) increased glucose metabolism and decreased fatty acid oxidation in primary cardiomyocytes, heart lysates and perfused hearts; 3) decreased complex II activity and 4) improved survival of cardiomyocytes following hypoxia and oxidative stress. Based on these data, we hypothesize that HN treatment will improve cardiac function in mouse and swine models of MI-R injury through its unique ability to induce metabolic adaptations to favor glucose utilization in cardiac myocytes, and decrease ROS through a combination of decreased FAO and complex II activity, thereby limiting acute myocardial cell death, and preventing the progression to HF. In this grant application, we will delineate the optimal dose and cardioprotective efficacy of HN in clinically relevant swine and murine models of MI-R injury and HF, and elucidate the mechanisms that underlie HN?s cardioprotective effects on the I-R myocardium. Results from these experiments may potentially have a tremendous impact in treating cardiovascular diseases. HN may provide a much-needed therapeutic option for patients to protect the myocardium from I-R injury, and prevent the progression to HF.